In this study, the authors have attempted to associate long-range circuit dysfunction with AD pathogenesis using large-scale calcium fluorescence imaging. The imaging techniques appear quite sound, and the idea of focusing on inhibitory neurons is logical.
My concern is the Tg mouse models used. They overexpress mutant APP and PS. Overexpression of membrane proteins containing 1 and 9 TM domains, respectively, could induce non-specific ER stress and explain the phenotypes observed in the study.
Mice overexpressing WT APP and PS at the same host loci with the same copy numbers of transgenes, rather than simple WT mice, would make appropriate negative controls, but such mice are practically difficult to engineer. The concern about proper negative control is significant, because overexpression of APP and PS transgenes results in the destruction of at least two gene loci in the host animals and may, in principle, generate artificial phenotypes. It is surprising that none of the Tg mice, to my knowledge, have been sequenced for defects.
APP interacts with kinesin via JIP-1, so APP overexpression may perturb axonal transport causing axonal sprouting. In addition, APP overexpression also results in overproduction of non-Aβ APP fragments. In particular, CTF-β, which does not accumulate much in human AD brain, is known to be more toxic than Aβ. The amount of excess CTF-β in the Tg mice should be visualized by western blotting.
Based on these points, I would suggest that the authors might want to examine whether their main findings are the result of APP and PS overexpression and not innate disease processes. We are willing to provide free to academic scientists our model mice that overproduce Aβ42 without overexpressing APP or PS1 (Saito et al., 2014). Right now, more than 130 laboratories across the world are using these mice. We estimate that approximately 60 percent of the phenotypes in conventional APP Tg mice are artifacts. I invite the authors, and other scientists experimentally working on AD in transgenic mouse models, to recognize, and take steps to correct, the APP overexpression paradigm.
Finally, AD is not AD in the absence of tauopathy and neurodegeneration. Thus, mouse models showing Aβ amyloidosis without tauopathy are models of preclinical AD. By definition, preclinical AD is neurologically asymptomatic, so the experimental “cognitive impairment” observed in the preclinical AD models is of less significance than neuropathologies in clinical terms. We must quickly move beyond overexpression artifacts and focus more attention on moving forward to identify the elements linking the Aβ amyloidosis to tauopathy and neurodegeneration.
References:
Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, Iwata N, Saido TC.
Single App knock-in mouse models of Alzheimer's disease.
Nat Neurosci. 2014 May;17(5):661-3. Epub 2014 Apr 13
PubMed.
Comments
RIKEN Center for Brain Science
In this study, the authors have attempted to associate long-range circuit dysfunction with AD pathogenesis using large-scale calcium fluorescence imaging. The imaging techniques appear quite sound, and the idea of focusing on inhibitory neurons is logical.
My concern is the Tg mouse models used. They overexpress mutant APP and PS. Overexpression of membrane proteins containing 1 and 9 TM domains, respectively, could induce non-specific ER stress and explain the phenotypes observed in the study.
Mice overexpressing WT APP and PS at the same host loci with the same copy numbers of transgenes, rather than simple WT mice, would make appropriate negative controls, but such mice are practically difficult to engineer. The concern about proper negative control is significant, because overexpression of APP and PS transgenes results in the destruction of at least two gene loci in the host animals and may, in principle, generate artificial phenotypes. It is surprising that none of the Tg mice, to my knowledge, have been sequenced for defects.
APP interacts with kinesin via JIP-1, so APP overexpression may perturb axonal transport causing axonal sprouting. In addition, APP overexpression also results in overproduction of non-Aβ APP fragments. In particular, CTF-β, which does not accumulate much in human AD brain, is known to be more toxic than Aβ. The amount of excess CTF-β in the Tg mice should be visualized by western blotting.
Based on these points, I would suggest that the authors might want to examine whether their main findings are the result of APP and PS overexpression and not innate disease processes. We are willing to provide free to academic scientists our model mice that overproduce Aβ42 without overexpressing APP or PS1 (Saito et al., 2014). Right now, more than 130 laboratories across the world are using these mice. We estimate that approximately 60 percent of the phenotypes in conventional APP Tg mice are artifacts. I invite the authors, and other scientists experimentally working on AD in transgenic mouse models, to recognize, and take steps to correct, the APP overexpression paradigm.
Finally, AD is not AD in the absence of tauopathy and neurodegeneration. Thus, mouse models showing Aβ amyloidosis without tauopathy are models of preclinical AD. By definition, preclinical AD is neurologically asymptomatic, so the experimental “cognitive impairment” observed in the preclinical AD models is of less significance than neuropathologies in clinical terms. We must quickly move beyond overexpression artifacts and focus more attention on moving forward to identify the elements linking the Aβ amyloidosis to tauopathy and neurodegeneration.
References:
Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, Iwata N, Saido TC. Single App knock-in mouse models of Alzheimer's disease. Nat Neurosci. 2014 May;17(5):661-3. Epub 2014 Apr 13 PubMed.
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